Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the μ-opioid receptor

Frank Porreca, Shannon E. Burgess, Luis R. Gardell, Todd W. Vanderah, T. Philip Malan, Michael H. Ossipov, Douglas A. Lappi, Josephine Lai

Research output: Contribution to journalArticle

212 Scopus citations

Abstract

Neurons in the rostroventromedial medulla (RVM) project to spinal loci where the neurons inhibit or facilitate pain transmission. Abnormal activity of facilitatory processes may thus represent a mechanism of chronic pain. This possibility and the phenotype of RVM cells that might underlie experimental neuropathic pain were investigated. Cells expressing μ-opioid receptors were targeted with a single microinjection of saporin conjugated to the μ-opioid agonist dermorphin; unconjugated saporin and dermorphin were used as controls. RVM dermorphin-saporin, but not dermorphin or saporin, significantly decreased cells expressing μ-opioid receptor transcript. RVM dermorphin, saporin, or dermorphin-saporin did not change baseline hindpaw sensitivity to non-noxious or noxious stimuli. Spinal nerve ligation (SNL) injury in rats pretreated with RVM dermorphin-saporin failed to elicit the expected increase in sensitivity to non-noxious mechanical or noxious thermal stimuli applied to the paw. RVM dermorphin or saporin did not alter SNL-induced experimental pain, and no pretreatment affected the responses of sham-operated groups. This protective effect of dermorphin-saporin against SNL-induced pain was blocked by β-funaltrexamine, a selective μ-opioid receptor antagonist, indicating specific interaction of dermorphin-saporin with the μ-opioid receptor. RVM microinjection of dermorphin-saporin, but not of dermorphin or saporin, in animals previously undergoing SNL showed a time-related reversal of the SNL-induced experimental pain to preinjury baseline levels. Thus, loss of RVM μ receptor-expressing cells both prevents and reverses experimental neuropathic pain. The data support the hypothesis that inappropriate tonic-descending facilitation may underlie some chronic pain states and offer new possibilities for the design of therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)5281-5288
Number of pages8
JournalJournal of Neuroscience
Volume21
Issue number14
DOIs
StatePublished - Jul 15 2001

Keywords

  • Descending facilitation
  • Neuropathic
  • Neuropathic pain
  • ON cells
  • RVM
  • Saporin
  • μ-opioid receptors

ASJC Scopus subject areas

  • Neuroscience(all)

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